strategies for cardiomyopathy evaluation genotyping ... 2020/acc... · heart rhythm....

Cardiologists beware: clinical limitations of genotyping- versus sequencing-based strategies for cardiomyopathy evaluation

Tom Callis, PhDClinical Science Liaison, Invitae

Presented at ACC.20/WCC Virtual in theHighlighted Original Research: Heart Failure and Cardiomyopathies and the Year in Review Session

© 2020 Invitae Corporation. All Rights Reserved.

Disclosures

2

Employee and stockholder of Invitae Corporation


Objectives

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● Recognize the spectrum of genetic tests available to clinicians and consumers today

● Determine how often individuals with genotype positive cardiomyopathy could be falsely reassured by partial screening tests

● Describe the importance of understanding the limitations of different testing methodologies

© 2020 Invitae Corporation. All Rights Reserved. 4

The number of genetic tests is growing rapidly and includes FDA-authorized direct-to-consumer (DTC) tests and hybrid models where consumers order laboratory-developed tests (LDTs) with physician support.

Number of tests submitted to the NIH Genetic Testing Registry1

References: 1) Genetic Testing Registry (GTR) - NCBI. [cited 19 Mar 2020]. Available: https://www.ncbi.nlm.nih.gov/gtr/


Molecular DNA testing methods include:● DNA chip analysis● Sanger sequencing● Allele-specific PCR ● MLPA ● Chromosomal microarray analysis● Next-generation sequencing

○ Gene panels○ Exome sequencing○ Genome sequencing○ Copy number variants

Across the spectrum of testing available, methods vary and different testing modalities are most appropriate for different types of variants.

The clinical limitations each modality are not always well-understood by non-specialists nor precisely defined among specialists.

.

Different testing modalities have inherent strengths and weaknesses, and may include the detection of:

● Known or novel variants● Single, few or many variants● Small or large variants● Simple or complex variants


Hypertrophic cardiomyopathy● >40 disease-causing genes1

Dilated cardiomyopathy● >30 disease-causing genes2

Pathogenic and likely pathogenic variants:3

● MYH7: >300 variants already known● MYBPC3: >500 variants already known

Recently, a limited variant screening strategy for 9 pathogenic or likely pathogenic (P/LP) cardiomyopathy variants in MYH7 and MYBPC3 was made available to consumers as a LDT through a hybrid ordering model.

References: 1) Cirino AL, Ho C. Hypertrophic Cardiomyopathy Overview. GeneReviews. University of Washington, Seattle; 2008. Last Update: June 6, 2019. 2) Hershberger RE, Morales A. Dilated Cardiomyopathy Overview. GeneReviews. University of Washington, Seattle; 2007. Last Update: August 23, 2018. 3) Landrum MJ, Lee JM, Benson M, Brown GR, Chao C, Chitipiralla S, et al. ClinVar: improving access to variant interpretations and supporting evidence. Nucleic Acids Res. 2018;46: D1062–D1067.

Cardiomyopathies are genetically heterogeneous involving many genes and thousands of variants


Genetic evaluation is recommended by all major cardiology professional societies to improve the diagnosis and management of cardiomyopathy patients and family members.1-4

References: 1) Gersh BJ et al. 2011 ACCF/AHA guideline for the diagnosis and treatment of hypertrophic cardiomyopathy: Executive summary. J Am. Coll Cardiol. 2011;58:2703-38. 2) Ackerman MJ et al. HRS/EHRA expert consensus statement on the state of genetic testing for the channelopathies and cardiomyopathies. Heart Rhythm. 2011;8;1308-39. 3) Al-Khatib SM et al. 2017 AHA/ACC/HRS Guideline for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: A report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol. 2018;72:e91-e220. 4) Hershberger, RE et al. Genetic Evaluation of Cardiomyopathy-A Heart Failure Society of America Practice Guideline. J. Card. Fail. 2018;24,281-302.


Objective of this study

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● Determine how often screening for only the 9 specific variants in just two genes, MYH7 and MYBPC3, would miss other P/LP variants and falsely reassure individuals at risk for cardiomyopathy


Methods

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Analyzed de-identified data from two indication-based cohorts:

● 5,743 patients of multiple ethnicities referred by healthcare providers referred for HCM testing of up to 60 genes

● 8,754 patients of multiple ethnicities referred by healthcare providers referred for comprehensive cardiomyopathy testing of up to 106 genes


Methods

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HCM testing referral cohort

5743

Full gene sequencing and

CNV analysis of up to 60 genes

Compare to genotyping of 9

variants in MYH7 and MYBPC3

Comprehensive cardiomyopathy referral cohort

8754

Full gene sequencing and

CNV analysis of up to 106 genes

Compare to genotyping of 9

variants in MYH7 and MYBPC3


Results

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The yield of clinical testing by sequencing was 22.4% (1286/5743) in the HCM group and 19.1% (1673/8754) in the comprehensive cardiomyopathy group for P/LP variants within the genes analyzed.

In contrast, the calculated yield of a genotyping screen reporting 9 specific variants in these same groups was, respectively, 1.5% (87/5743) and 0.4% (33/8754).

Comprehensive cardiomyopathy cohort

HCM referral cohort


Conclusions

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● These results predict that 96% of individuals with genetically-positive cardiomyopathy would be falsely reassured by a negative result through a limited genotyping testing strategy.

● It is paramount for clinicians to avoid interpreting such uninformative results as an “all-clear” that would preclude patients and at-risk family members from receiving appropriate care and monitoring based on their true risk.


Acknowledgements

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Hypertrophic Cardiomyopathy Association (HCMA)● Lisa Salberg

Invitae● Rebecca Truty, PhD● Edward D. Esplin, MD, PhD, FACMG, FACP● Ana Morales, MS, CGC● Matteo Vatta, PhD, FACMG● Robert L. Nussbaum, MD, FACMG, FACP

Thank you

strategies for cardiomyopathy evaluation genotyping ... 2020/acc... · heart rhythm....

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